المؤلفون: Monjazeb, Arta M, Daly, Megan E, Luxardi, Guillaume, Maverakis, Emanual, Merleev, Alexander A, Marusina, Alina I, Borowsky, Alexander, Mirhadi, Amin, Shiao, Stephen L, Beckett, Laurel, Chen, Shuai, Eastham, David, Li, Tianhong, Vick, Logan V, McGee, Heather M, Lara, Frances, Garcia, Leslie, Morris, Leigh Anne, Canter, Robert J, Riess, Jonathan W, Schalper, Kurt A, Murphy, William J, Kelly, Karen

المصدر: Nature Communications. 14(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Lung Cancer, Clinical Research, Cancer, Clinical Trials and Supportive Activities, Lung, Evaluation of treatments and therapeutic interventions, 6.5 Radiotherapy and other non-invasive therapies, 6.1 Pharmaceuticals, Good Health and Well Being, Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Small Cell Lung Carcinoma, Radiosurgery

الوصف: Stereotactic ablative radiotherapy (SABR) is a standard-of-care for medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third of patients progress and chemotherapy is rarely used in this population. We questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to standard-of-care SABR can improve outcomes. We initiated a multi-institutional single-arm phase I study (NCT02599454) enrolling twenty patients with the primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety and efficacy; and exploratory mechanistic correlatives. Treatment is well tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals include early responses (after 2 cycles of ICI, before initiation of SABR) in 17% of patients. Biomarkers of functional adaptive immunity, including T cell activation in the tumor and response to ex-vivo stimulation by circulating T cells, are highly predictive of benefit. These results require validation and are being tested in a phase III randomized trial.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0jq19596Test

المؤلفون: Shiao, Stephen L., Gouin, Kenneth H., Ing, Nathan, Ho, Alice, Basho, Reva, Shah, Aagam, Mebane, Richard H., Zitser, David, Martinez, Andrew, Mevises, Natalie-Ya, Ben-Cheikh, Bassem, Henson, Regina, Mita, Monica, McAndrew, Philomena, Karlan, Scott, Giuliano, Armando, Chung, Alice, Amersi, Farin, Dang, Catherine, Richardson, Heather, Shon, Wonwoo, Dadmanesh, Farnaz, Burnison, Michele, Mirhadi, Amin, Zumsteg, Zachary S., Choi, Rachel, Davis, Madison, Lee, Joseph, Rollins, Dustin, Martin, Cynthia, Khameneh, Negin H., McArthur, Heather, Knott, Simon R.V.

المساهمون: US Department of Defense, National Cancer Institute, Breast Cancer Research Foundation, California Breast Cancer Research Program

المصدر: Cancer Cell ; volume 42, issue 1, page 70-84.e8 ; ISSN 1535-6108

مصطلحات موضوعية: Cancer Research, Oncology

الإتاحة: https://doi.org/10.1016/j.ccell.2023.12.012Test
https://api.elsevier.com/content/article/PII:S1535610823004403?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1535610823004403?httpAccept=text/plainTest

المؤلفون: Shiao, Stephen L, Kershaw, Kathleen M, Limon, Jose J, You, Sungyong, Yoon, Junhee, Ko, Emily Y, Guarnerio, Jlenia, Potdar, Alka A, McGovern, Dermot PB, Bose, Shikha, Dar, Tahir B, Noe, Paul, Lee, Jung, Kubota, Yuzu, Maymi, Viviana I, Davis, Madison J, Henson, Regina M, Choi, Rachel Y, Yang, Wensha, Tang, Jie, Gargus, Matthew, Prince, Alexander D, Zumsteg, Zachary S, Underhill, David M

المصدر: Cancer Cell. 39(9)

مصطلحات موضوعية: Vaccine Related, Breast Cancer, Digestive Diseases, Cancer, Animals, Antifungal Agents, Bacteria, Breast Neoplasms, Combined Modality Therapy, Down-Regulation, Female, Fungi, Gastrointestinal Microbiome, Gene Expression Regulation, Neoplastic, Humans, Lectins, C-Type, Melanoma, Mice, Symbiosis, T-Lymphocytes, Tumor-Associated Macrophages, Up-Regulation, Xenograft Model Antitumor Assays, T cells, bacteria, dectin-1, fungi, immunotherapy, macrophages, microbiome, mycobiome, radiation, tumor immunology, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses. Antibiotic-mediated depletion or gnotobiotic exclusion of fungi enhances responsiveness to radiation, whereas antibiotic-mediated depletion of bacteria reduces responsiveness and is associated with overgrowth of commensal fungi. Further, elevated intratumoral expression of Dectin-1, a primary innate sensor of fungi, is negatively associated with survival in patients with breast cancer and is required for the effects of commensal fungi in mouse models of radiation therapy.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0vx6q7qjTest

المؤلفون: Monjazeb, Arta M, Schalper, Kurt A, Villarroel-Espindola, Franz, Nguyen, Anthony, Shiao, Stephen L, Young, Kristina

المصدر: Seminars in Radiation Oncology. 30(2)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Orphan Drug, Vaccine Related, Cancer, Immunization, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Adaptive Immunity, Humans, Immunity, Innate, Immunotherapy, Neoplasms, Tumor Microenvironment, Oncology & Carcinogenesis, Oncology and carcinogenesis

الوصف: A malignant tumor consists of malignant cells as well as a wide array of normal host tissues including stroma, vasculature, and immune infiltrate. The interaction between cancer and these host tissues is critical as these host tissues play a variety of roles in supporting or resisting disease progression. Radiotherapy (RT) has direct effects on malignant cells, but, also, critically important effects on these other components of the tumor microenvironment (TME). Given the growing role of immune checkpoint inhibitors and other immunotherapy strategies, understanding how RT affects the TME, particularly the immune compartment, is essential to advance RT in this new era of cancer therapy. The interactions between RT and the TME are complex, affecting the innate and adaptive arms of the immune system. RT can induce both proinflammatory effects and immune suppressive effects that can either promote or impede antitumor immunity. It is likely that the initial proinflammatory effects of RT eventually lead to rebound immune-suppression as chronic inflammation sets in. The exact kinetics and nature of how RT changes the TME likely depends on timing, dose, fractionation, site irradiated, and tumor type. With increased understanding of the effects of RT on the TME, in the future it is likely that we will be able to personalize RT by varying the dose, site, and timing of intervention to generate the desired response to partner with immunotherapy strategies.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9gd7m8rkTest

المؤلفون: Grausam, Katie B, Hatanaka, Emily, Dar, Tahir B, Fernandez Pacheco, David Rincon, Breunig, Joshua J, Shiao, Stephen L

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2023-sitc2023.0458Test

المؤلفون: Nguyen, Anthony T, Dar, Tahir B, Viramontes, Jolene, Stevens, Satchel, Jang, Julie, Ko, Emily, Chung, Eric M, Zhang, Samuel, Atkins, Katelyn M, Kamrava, Mitchell, Sandler, Howard M, Guarnerio, Jlenia, Knott, Simon, Zumsteg, Zachary, Underhill, David M, Shiao, Stephen L

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2023-sitc2023.0892Test

المؤلفون: Tuli, Richard, Shiao, Stephen L, Nissen, Nicholas, Tighiouart, Mourad, Kim, Sungjin, Osipov, Arsen, Bryant, Miranda, Ristow, Lindsey, Placencio-Hickok, Veronica, Hoffman, David, Rokhsar, Sepehr, Scher, Kevin, Klempner, Samuel J, Noe, Paul, Davis, MJ, Wachsman, Ashley, Lo, Simon, Jamil, Laith, Sandler, Howard, Piantadosi, Steven, Hendifar, Andrew

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Trials and Supportive Activities, Digestive Diseases, Genetics, Pancreatic Cancer, Clinical Research, Cancer, Rare Diseases, 6.5 Radiotherapy and other non-invasive therapies, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Aged, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Combined Modality Therapy, Deoxycytidine, Female, Humans, Male, Microsatellite Instability, Middle Aged, Mutation, Neoplasm Metastasis, Neoplasm Staging, Pancreatic Neoplasms, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Prognosis, Radiotherapy, Treatment Outcome, Gemcitabine, Parp inhibitor, Radiation, Pancreas cancer, Veliparib, Public Health and Health Services, Clinical sciences, Epidemiology

الوصف: BackgroundLocally advanced pancreatic cancer (LAPC) has a dismal prognosis with current treatment modalities and one-third of patients die from local progression of disease. Preclinical studies with orthotopic PC demonstrated dramatic synergy between radiotherapy (RT) and the poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi), veliparib. We conducted a phase I trial of gemcitabine, radiotherapy and dose-escalated veliparib in LAPC.MethodsThis was a single institution investigator-initiated open-label, single-arm phase 1 clinical trial (NCT01908478). Weekly gemcitabine with daily IMRT and veliparib dose escalated using a Bayesian adaptive design were administered in treatment naïve LA or borderline resectable PC. The primary end point was identification of the MTD. Secondary endpoints included efficacy, characterization of PAR levels using ELISA, DDR alterations with targeted next generation sequencing and transcriptome analysis, tumor mutation burden (TMB) and microsatellite instability (MSI) status.FindingsThirty patients were enrolled. The MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m2 and RT (36 Gy/15 fractions). Sixteen DLTs were identified in 12 patients. Grade ≥ 3 adverse events included lymphopenia (96%) and anemia (36%). Median OS for all patients was 15 months. Median OS for DDR pathway gene altered and intact cases was 19 months (95% CI: 6.2-27.2) and 14 months (95% CI: 10.0-21.8), respectively. There were no significant associations between levels of PAR, TMB, or MSI with outcomes. The DDR transcripts PARP3 and RBX1 significantly correlated with OS.InterpretationThis is the first report of a PARPi-chemoradiotherapy combination in PC. The regimen was safe, tolerable at the RP2D, and clinically active as an upfront treatment strategy in patients biologically unselected by upfront chemotherapy. Expression of the DDR transcripts, PARP3 and RBX1, were associated with OS suggesting validation in a follow up phase 2 study. FUND: Phase One Foundation; National Institutes of Health [1R01CA188480-01A1, P01 CA098912]. Veliparib was provided by Abbvie.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5hx0f9d9Test

المؤلفون: Marciscano, Ariel E, Walker, Joshua M, McGee, Heather M, Kim, Michelle M, Kunos, Charles A, Monjazeb, Arta M, Shiao, Stephen L, Tran, Phuoc T, Ahmed, Mansoor M

المصدر: Journal for ImmunoTherapy of Cancer. 6(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Vaccine Related, Rare Diseases, Orphan Drug, Cancer, Immunization, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Antineoplastic Agents, Immunological, Biomarkers, Tumor, Combined Modality Therapy, Humans, Immunotherapy, Neoplasms, Radiation Oncology, Radiation oncology, Radiation therapy, Radiotherapy, Immune checkpoint blockade, Immune checkpoint inhibitors, ASTRO, SITC, Combinations, Oncology and carcinogenesis

الوصف: Radiotherapy (RT) has been a fundamental component of the anti-cancer armamentarium for over a century. Approximately half of all cancer patients are treated with radiotherapy during their disease course. Over the two past decades, there has been a growing body of preclinical evidence supporting the immunomodulatory effects of radiotherapy, particularly when combined with immunotherapy, but only anecdotal clinical examples existed until recently. The renaissance of immunotherapy and the recent U.S. Food and Drug Administration (FDA) approval of several immune checkpoint inhibitors (ICIs) and other immuno-oncology (IO) agents in multiple cancers provides the opportunity to investigate how localized radiotherapy can induce systemic immune responses. Early clinical experiences have demonstrated feasibility of this approach but additional preclinical and clinical investigation is needed to understand how RT and immunotherapy can be optimally combined.To address questions that are critical to successful incorporation of radiation oncology into immunotherapy, the American Society for Radiation Oncology (ASTRO), the Society for Immunotherapy of Cancer (SITC) and the National Cancer Institute (NCI) organized a collaborative scientific workshop, Incorporating Radiation Oncology into Immunotherapy, that convened on June 15 and 16 of 2017 at the Natcher Building, NIH Campus in Bethesda, Maryland. This report summarizes key data and highlights from each session.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5tc7r01qTest

المؤلفون: Miyaguchi, Ken, Wang, Hongqiang, Black, Keith L., Shiao, Stephen L., Wang, Rongfu, Yu, John S.

المصدر: Scientific Reports ; volume 13, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: Naïve T cells become effector T cells following stimulation by antigen-loaded dendritic cells (DCs) and sequential cytokine activation. We aimed to develop procedures to efficiently activate T cells with tumor-associated antigens (TAAs) to glioblastoma (GBM) stem cells. To remove antigen presentation outside of the immunosuppressive tumor milieu, three different glioma stem cell (GSC) specific antigen sources to load DCs were compared in their ability to stimulate lymphocytes. An activated T cell (ATC) protocol including cytokine activation and expansion in culture to target GSCs was generated and optimized for a planned phase I clinical trial. We compared three different antigen-loading methods on DCs to effectively activate T cells, which were GBM patient-derived GSC-lysate, acid-eluate of GSCs and synthetic peptides derived from proteins expressed in GSCs. DCs derived from HLA-A2 positive blood sample were loaded with TAAs. Autologous T cells were activated by co-culturing with loaded DCs. Efficiency and cytotoxicity of ATCs were evaluated by targeting TAA-pulsed DCs or T2 cells, GSCs, or autologous PHA-blasts. Characteristics of ATCs were evaluated by Flow Cytometry and ELISpot assay, which showed increased number of ATCs secreting IFN-γ targeting GSCs as compared with non-activated T cells and unloaded target cells. Neither GSC-lysate nor acid-eluate loading showed enhancement in response of ATCs but the synthetic peptide pool showed significantly increased IFN-γ secretion and increased cytotoxicity towards target cells. These results demonstrate that ATCs activated using a TAA synthetic peptide pool efficiently enhance cytotoxicity specifically to target cells including GSC.

الإتاحة: https://doi.org/10.1038/s41598-022-27184-wTest
https://www.nature.com/articles/s41598-022-27184-w.pdfTest
https://www.nature.com/articles/s41598-022-27184-wTest

المؤلفون: Kirkness, Jason P., Dusting, Jonathan, Eikelis, Nina, Pirakalathanan, Piraveen, DeMarco, John, Shiao, Stephen L., Fouras, Andreas

المصدر: Frontiers in Medical Technology ; volume 5 ; ISSN 2673-3129

مصطلحات موضوعية: Industrial and Manufacturing Engineering, Metals and Alloys, Strategy and Management, Mechanical Engineering

الوصف: Introduction X-ray Velocimetry (XV) ventilation analysis is a 4-dimensional imaging-based method for quantifying regional ventilation, aiding in the assessment of lung function. We examined the performance characteristics of XV ventilation analysis by examining correlation to spirometry and measurement repeatability. Methods XV analysis was assessed in 27 patients receiving thoracic radiotherapy for non-lung cancer malignancies. Measurements were obtained pre-treatment and at 4 and 12-months post-treatment. XV metrics such as ventilation defect percent (VDP) and regional ventilation heterogeneity (VH) were compared to spirometry at each time point, using correlation analysis. Repeatability was assessed between multiple runs of the analysis algorithm, as well as between multiple breaths in the same patient. Change in VH and VDP in a case series over 12 months was used to determine effect size and estimate sample sizes for future studies. Results VDP and VH were found to significantly correlate with FEV 1 and FEV 1 /FVC (range: −0.36 to −0.57; p < 0.05). Repeatability tests demonstrated that VDP and VH had less than 2% variability within runs and less than 8% change in metrics between breaths. Three cases were used to illustrate the advantage of XV over spirometry, where XV indicated a change in lung function that was either undetectable or delayed in detection by spirometry. Case A demonstrated an improvement in XV metrics over time despite stable spirometric values. Case B demonstrated a decline in XV metrics as early as 4-months, although spirometric values did not change until 12-months. Case C demonstrated a decline in XV metrics at 12 months post-treatment while spirometric values remained normal throughout the study. Based on the effect sizes in each case, sample sizes ranging from 10 to 38 patients would provide 90% power for future studies aiming to detect similar changes. Conclusions The performance and safety of XV analysis make it ideal for both clinical and research applications across most ...

الإتاحة: https://doi.org/10.3389/fmedt.2023.1148310Test